This invention relates to novel pyrazoloquinolinone derivatives. These compounds are useful as inhibitors of protein kinase C (PKC), and are thus useful in the treatment of neuropathic pain, Inflammatory Pain, Diabetic Neuropathy or the like in mammalian, especially human. The present invention also relates to a pharmaceutical composition comprising the above compounds.
Protein kinase C (PKC) was originally identified as a phospholipid-dependent, calcium- and diacylglycerol (DAG)-stimulated protein serine/threonine kinase. PKC is categorized into three groups, conventional PKC (xcex1, xcex21, xcex22, xcex3), novel PKC (xcex4, xcex5, xcex7, xcex8) and atypical PKC ("igr", xcex6) based on the structural difference that foster differences on calcium and lipid binding properties. Early studies demonstrated that PKC is activated in vivo by the receptor-induced second messenger DAG/tumor promoting phorbol esters and calcium. This quickly established PKC as a key regulator of cell growth and differentiation, cell survival, neurotransmission and carcinogenesis(See Bell, R. M. and Burns, D. J., J. Biol. Chem. 266: 4661-4664 (1991); Nishizuka, Y. Science 258: 607-614 (1992)).
Protein kinase C (PKC) inhibitors are found to be useful for the treatment of a variety of diseases such as neuropathic pain, acute or chronic inflammatory pain, diabetic neuropathy, sepsis, shock, ARDS, asthma, HIV infection, Alzheimer, gastric ulcer, drug resistance, diabetes and cerebral ischemia. (See Science, 1997, 278, 279-283; European J. Pharmacology, 1999, 372, 221-228; ibid, 2000, 403, 81-85; Shock, 1998, 9, 256-60; J. Biol. Chem., 1997, 272, 12289-94; Brain Research, 1997, 769, 287-295; Digestion, 1998, 59, 40-46; Biochemical Pharmacology, 1999, 58, 1587-92; Am. J. Physiology, 1999, 276, 691-699; and Brain Research, 1998, 779, 254-58).
WO 97/40035 discloses N-substituted azaheterocyclic carboxylic acids and esters. WO99/36421 discloses Tricyclic N-acylated tricyclic azaheterorings compounds.
It would be desirable if there were provided protein kinase C (PKC) inhibitors which have more protein kinase C (PKC) inhibitory activities.
The present invention provides a compound of the following formula: 
or the pharmaceutically acceptable salts thereof wherein
the dashed lines represent optional double bonds;
R1 is C1-4 alkyl;
R2 is H, amino, mono- or di-(C1-4alkyl)amino or C1-3 alkyl-(Oxe2x95x90)CNHxe2x80x94;
R3 is H, halo-CH2xe2x80x94, R4(R5)NCH2xe2x80x94, R6(R7)NC(xe2x95x90O)CH2xe2x80x94, cyano-CH2xe2x80x94, Q1CH2xe2x80x94, Q1-(Oxe2x95x90)CCH2xe2x80x94, C2-8 alkyl or Q1-, wherein said C2-8 alkyl is optionally substituted with up to 3 substituents selected from halo, C1-3 alkyl, R4(R5)N, C1-4 alkylsulfonylamino, C1-4 alkylthio, R6(R7)NC(xe2x95x90O)xe2x80x94, cyano, Q1-, Q1-(Oxe2x95x90)Cxe2x80x94 and Q1-C1-4 alkyl-Oxe2x80x94;
Y1, Y2, Y3 and Y4 are independently selected from hydrogen, halo, C1-4 alkyl, C1-4 alkyl-Oxe2x80x94, C1-4 alkylthio, Q1-, R6(R8)Nxe2x80x94, R6N(R7)C(xe2x95x90O)xe2x80x94, C1-4alkyl-O(Oxe2x95x90)CCHxe2x95x90CHxe2x80x94, Q1-(Oxe2x95x90)CNHxe2x80x94 and R6OC(xe2x95x90O)xe2x80x94, wherein said C1-4alkyl is optionally substituted with up to 2 substituents selected from Q1, Q2-, R6(R7)Nxe2x80x94, cyano, hydroxy and R6(R7)NC(xe2x95x90O)xe2x80x94;
Y5, Y6, Y7 and Y8 are hydrogen or are absent;
C1, C2, C3 and C4 are carbon atom;
R4 is H, C1-7 alkyl, HOxe2x80x94C1-4 alkyl, Q1-, Q1-C1-4alkyl-, cyano- C1-4 alkyl- or R6(R7)N C1-4 alkyl-;
R5 is H, C1-7alkyl, HOxe2x80x94C1-4 alkyl or Q1-;
R6 and R7 are independently selected from H and C1-4 alkyl
R8 is aryl or heteroaryl;
Q1 is a 4-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, amino, hydroxy, R6(R7)NC1-4alkyl- or R6(R7)NC1-4alkyl-Oxe2x80x94; and
Q2 is a 5-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 3 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4alkyl-, hydroxy, C1-4 alkoxy, nitro, amino, cyano, R6(R7)Nxe2x80x94C1-4alkyl-, R6(R7)Nxe2x80x94C1-4alkyl-Oxe2x80x94, R6(R7)N(Oxe2x95x90)Cxe2x80x94 or R6O(Oxe2x95x90)Cxe2x80x94;
with the proviso that when R1 is methyl and R2 and R3 are H, Y1, Y2, Y3 and Y4 are not H simultaneously; and when R1 is methyl and R2 and R3 are H, Y2 is not chloro.
The pyrazoloquinolinone compounds of this invention have protein kinase C (PKC) inhibitory activities and are thus useful for the treatment of disease conditions mediated by PKC activities.
Thus, the present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by protein kinase C, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of neuropathic pain, acute or chronic inflammatory pain, auditory deficiency (synaptic repair), hypertension, forcal celebral ischemia, pulmonary fibrosis, diabetes, immune disease, colonic repair, drug resistance (MDR regulation), Alzheimer, sepsis, shock, ARDS, inflammation, ischemia, gastric acid regulation, diabetic neuropathy, asthma, HIV infection, gastric ulcer or cerebral ischemia or the like, which comprises a therapeutically effective amount of the imidazopyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of disease conditions mediated by protein kinase C activities, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Further, the present invention provides a method for the treatment of the disease conditions as mentioned above.
As used herein, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94, including, but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiary-butoxy.
As used herein, the term xe2x80x9carylxe2x80x9d means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 11 carbon atoms including, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl, preferably phenyl and naphthyl.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d means a 5- to 10-membered monocyclic or bicyclic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. Examples of the heteroaryl include, but are not limited to, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl quinoxalinyl and the like.
As used herein, the term xe2x80x9c4-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 4 heteroatoms selected from O, N and Sxe2x80x9d may be, for example, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl, azetidinyl, furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thienyl, pyridyl, piperidyl (or piperidinyl), piperidino, oxazinyl, morpholinyl, morphorino, thiamorpholino, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, piperazino, triazinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, chromanyl, isochromanyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl.
As used herein, the term xe2x80x9c5-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 3 heteroatoms selected from O, N and Sxe2x80x9d may be, for example, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, pyranyl, thienyl, pyridyl, piperidyl (or piperidinyl), piperidino, oxazinyl, morpholinyl, morphorino, thiamorpholino, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, piperazino, homopiperazinyl, homopiperazino,triazinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, chromanyl, isochromanyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl.
In the compounds of formula (I),
R1 is preferably C1-2 alkyl, and most preferably R1 is methyl.
In the compounds of formula (I),
R2 is preferably R2 is H or amino, and most preferably R2 is H.
In the compounds of formula (I),
R3 is preferably H, halo-CH2xe2x80x94, R4(R5)NCH2xe2x80x94, R6(R7)NC(xe2x95x90O)CH2xe2x80x94, cyano-CH2xe2x80x94, Q1CH2xe2x80x94, Q1-(Oxe2x95x90)CCH2xe2x80x94, C2-6 alkyl or Q1-, wherein said C2-6 alkyl is optionally substituted with up to 3 substituents selected from halo, methyl, R4(R5)N, C1-2 alkylsulfonylamino, C1-2 alkylthio, R6(R7)NC(xe2x95x90O)xe2x80x94, cyano, Q1- and Q1-(Oxe2x95x90)Cxe2x80x94, wherein R4 is H, C1-6 alkyl, HOxe2x80x94C1-2 alkyl, Q1-, Q1-C1-3alkyl-, cyano-C1-2alkyl- or R6(R7)N C1-2alkyl-; R5 is H, C1-2alkyl, HOxe2x80x94C1-2 alkyl or Q1-; R6 and R7 are independently selected from H and C1-2 alkyl; and Q1 is a 4-10 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 2 heteroatoms selected from O and N, and is optionally substituted with halo, C1-2 alkyl, hydroxy, amino, R6(R7)N C1-2alkyl- or R6(R7)NC1-2alkyl-Oxe2x80x94, more preferably hydrogen, ethyl, butyl, hexyl, iodopentyl, carbamoylmethyl, methylthioethyl, (N,N-dimethylamino)ethyl, morpholinoethyl, (N,N-dimethylamino)butyl, (N,N-dimethylamino)hexyl, methansulfonylaminopropyl, (N-ethyl-N-methylamino)propyl, chloroethyl, aminoethyl, [(N,N-dimethylamino)methyl]phenyl, (N,N-dimethylamino)(methyl)propyl, (1-methyl-2-piperidinyl)ethyl, pyridylmethyl, cyanobutyl, 2-benzimidazolylmethyl, (N-methylamino)propyl, (1-methyl-2-pyrrolidinyl)ethyl, (1-azetidinyl)propyl, {N-methyl-N-[(pyridinyl)ethyl]amino}propyl, (N,N-diethylamino)propyl, [N-isopropyl-N-(methyl)amino]propyl, [N-(2-hydroxyethyl)-N-(isopropyl)amino]propyl, [N,N-bis(2-hydroxyethyl)amino]propyl, [N-(hydroxyethyl)-N-(methyl)aminopropyl, [N-ethyl-N-(propyl)amino]propyl, (4-methyl-1,4-diazepan-1-yl)propyl, [N-hexyl-N-(methyl)amino]propyl, [N-(cyanomethyl)-N-(propyl)amino]propyl, [N-[(diethylamino)ethyl]-N-(methyl)amino]propyl, [N-(cyanomethyl)-N-(methyl)amino]propyl, [N-methyl-N-(phenylethyl)amino]propyl, [N-ethyl-N-(hydroxyethyl)amino]propyl, (3,4-dihydro-2(1H)-isoquinolinyl)propyl, N-methyl-piperidyl, (N,N-dimethylamino)propyl, piperidyl, aminopropyl or cyanomethyl, more preferably, H, ethyl, n-butyl, n-hexyl, 5-iodopentyl, carbamoylmethyl, 2-methylthioethyl, 2-(N,N-dimethylamino)ethyl, 2-morpholinoethyl, 4-(N,N-dimethylamino)butyl, 6-(N,N-dimethylamino)hexyl, 3-methansulfonylaminopropyl, 3-(N-ethyl-N-methylamino)propyl, 2-chloroethyl, 2-aminoethyl, 4-[(N,N-dimethylamino)methyl]phenyl, 3-(N,N-dimethylamino)-2-methylpropyl, 2-(1-methyl-2-piperidinyl)ethyl, 3-pyridylmethyl, 4-cyanobutyl, 4-(1H-benzimidazol-2-ylmethyl), 3-(N-methylamino)propyl, 2-(1-methyl-2-pyrrolidinyl)ethyl, 3-(1-azetidinyl)propyl, 3-{N-methyl-N-[2-(2-pyridinyl)ethyl]amino}propyl, 3-(N,N-diethylamino)propyl, 3-[N-isopropyl-N-(methyl)amino]propyl, 3-[N-(2-hydroxyethyl)-N-(isopropyl)amino]propyl, 3-[N,N-bis(2-hydroxyethyl)amino]propyl, 3-[N-(2-hydroxyethyl)-N-(methyl)amino]propyl, 3-[N-ethyl-N-(propyl)amino]propyl, 3-(4-methyl-1,4-diazepan-1-yl)propyl, 3-[N-hexyl-N-(methyl)amino]propyl, 3-(N-cyanomethyl-N-propyl)aminopropyl, 3-[N-[2-(Nxe2x80x2,Nxe2x80x2-diethylamino)ethyl]-N-(methyl)amino]propyl, 3-[(N-cyanomethyl-N-methyl)amino]propyl, 3-[N-methyl-N-(2-phenylethyl)amino]propyl, 3-[N-ethyl-N-(2-hydroxyethyl)amino]propyl, 3-(3,4-dihydro-2(1H)-isoquinolinyl)propyl, N-methyl-4-piperidyl, 3-(N,N-dimethylamino)propyl, 4-piperidyl, 3-aminopropyl, cyanomethyl or 2-benzimidazolylmethyl, more preferably H, N-methyl-4-piperidyl, 3-N,N-dimethylpropyl, 4-piperidyl, 3-aminopropyl, cyanomethyl or 2-benzimidazolylmethyl, and most preferably H.
In the compounds of formula (I),
Y1, Y2, Y3 and Y4 are preferably independently selected from hydrogen, halo, C1-3 alkyl, C1-3 alkyl-Oxe2x80x94, C1-2 alkylthio, Q1-, R6(R8)Nxe2x80x94, R6N(R7)C(xe2x95x90O)xe2x80x94, C1-2 alkyl-O(Oxe2x95x90)CCHxe2x95x90CHxe2x80x94, Q1-(Oxe2x95x90)CNHxe2x80x94 and R6OC(xe2x95x90O)xe2x80x94, wherein said C1-3alkyl is optionally substituted with up to 2 substituents selected from Q1-, Q2-, R6(R7)Nxe2x80x94, cyano, hydroxy and R6(R7)NC(xe2x95x90O)xe2x80x94, wherein R6 and R7 are independently selected from H and C1-3alkyl; R8 is aryl; Q1 is a 4-10 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 2 heteroatoms selected from O and N, and is optionally substituted with halo, C1-2 alkyl, hydroxy, amino, R6(R7)N C1-2alkyl- or R6(R7)NC1-2alkyl-Oxe2x80x94; and Q2 is phenyl or pyridyl being optionally substituted with halo, C1-2 alkyl-, hydroxy, C1-2 alkyl-Oxe2x80x94, nitro, amino, cyano, R6(R7)Nxe2x80x94C1-2alkyl- or R6(R7)Nxe2x80x94C1-2alkyl-Oxe2x80x94, R6(R7)N(Oxe2x95x90)Cxe2x80x94 or R6O(Oxe2x95x90)Cxe2x80x94, more preferably independently selected from hydrogen, halo, C1-3 alkyl, C1-3 alkyl-Oxe2x80x94, C1-2 alkylthio, Q1-, R6(R8)Nxe2x80x94, R6N(R7)C(xe2x95x90O)xe2x80x94, C1-2 alkyl-O(Oxe2x95x90)CCHxe2x95x90CHxe2x80x94, Q1-(Oxe2x95x90)CNHxe2x80x94 and R6OC(xe2x95x90O)xe2x80x94, wherein said C1-3alkyl is optionally substituted with up to 2 substituents selected from Q1, Q2-, R6(R7)Nxe2x80x94, cyano, hydroxy and R6(R7)NC(xe2x95x90O)xe2x80x94, wherein R6 and R7 are independently selected from H, methyl and ethyl; R8 is phenyl; Q1 is phenyl, piperidyl, morpholino, pyridyl, benzimidazolyl, pyrrolidinyl, azetidinyl, diazepanyl or tetrahydroisoquinolyl being optionally substituted with halo, C1-2 alkyl, hydroxy, amino, R6(R7)N C1-2alkyl- or R6(R7)N C1-2alkyl-Oxe2x80x94; and Q2 is phenyl or pyridyl being optionally substituted with halo, C1-2 alkyl-, hydroxy, C1-2 alkyl-Oxe2x80x94, nitro, amino, cyano, R6(R7)Nxe2x80x94C1-2alkyl-, R6(R7)Nxe2x80x94C1-2 alkyl-Oxe2x80x94, R6(R7)N(Oxe2x95x90)Cxe2x80x94 or R6O(Oxe2x95x90)Cxe2x80x94, and most preferably independently selected from H, fluoro, chloro, bromo, methyl, ethyl, iso-propyl, aminopropyl, methoxy, benzyl, aminobenzyl, hydroxybenzyl, chlorobenzyl, cyanobenzyl, methoxybenzyl, (N,N-dimethylaminoethoxy)benzyl, nitrobenzyl, aminomethylbenzyl, aminoethylbenzyl, carbamoylbenzyl, carboxybenzyl, anilino, benzoylamino, hydroxy(phenyl)methyl, phenyl, aminophenyl, hydroxyphenyl, cyanoethyl, pyridylmethyl and ethoxycarbonylethenyl.
Y1 is more preferably H, methyl, ethyl, propyl, aminophenyl, hydroxyphenyl, methoxy, fluoro or chloro, more preferably H, ethyl, 4-aminophenyl, iso-propyl, 4-hydroxyphenyl, methoxy or fluoro, and most preferably H, ethyl or 4-aminophenyl.
Y2 is more preferably hydrogen, methyl, ethyl, propyl, benzyl, chlorobenzyl, benzoylamino, hydroxybenzyl, methoxybenzyl, (N,N-dimethylaminoethoxy)benzyl, aminopropyl, anilino, nitrobenzyl, aminomethylbenzyl, (aminoethyl)benzyl, aminobenzyl, cyanobenzyl, hydroxy(phenyl)methyl, hydroxyphenyl, cyanoethyl, pyridylmethyl, carbamoylbenzyl, carboxybenzyl, ethoxycarbonylethenyl or fluoro, more preferably hydrogen, 4-chlorobenzyl, benzoylamino, 3-chlorobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, benzyl, 3-aminopropyl, anilino, 4-hydroxybenzyl, 3-nitrobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, methyl, 2-aminomethylbenzyl, 2-(2-aminoethyl)benzyl, 2-aminobenzyl, 2-methoxybenzyl, 3-aminobenzyl, 3-aminomethylbenzyl, 4-cyanobenzyl, hydroxy(phenyl)methyl, 2-hydroxyphenyl (3-hydroxyphenyl, 2-cyanoethyl, ethyl, 3-pyridylmethyl, 3-carbamoylbenzyl, 3-carboxybenzyl, ethoxycarbonylethenyl, 2-carbamoylbenzyl or fluoro, and most preferably H, 4-chlorobenzyl, benzoylamino, 3-chlorobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, benzyl, 3-aminopropyl, anilino, 4-hydroxybenzyl, 3-nitrobenzyl, 3-methoxybenzyl or 2-chlorobenzyl.
Y3 is more preferably hydrogen, ethyl, methyl, methoxy or fluoro, more preferably hydrogen, methoxy or fluoro, and most preferably H.
Y4 is more preferably hydrogen, chloro, fluoro, bromo, methyl, ethyl, methoxy or phenyl, more preferably hydrogen, chloro, fluoro, bromo or ethyl, and most preferably H.
Preferred compounds of this invention are those of the formula (I) wherein
R1 is C1-2 alkyl;
R2 is H or amino;
R3 is H, halo-CH2xe2x80x94, R4(R5)NCH2xe2x80x94, R6(R7)NC(xe2x95x90O)CH2xe2x80x94, cyano-CH2xe2x80x94, Q1CH2xe2x80x94, (Oxe2x95x90)CCH2xe2x80x94, C2-6 alkyl or Q1-, wherein said C2-6 alkyl is optionally substituted with up to 3 substituents selected from halo, methyl, R4(R5)N, C1-2 alkylsulfonylamino, C1-2 alkylthio, R6(R7)NC(xe2x95x90O)xe2x80x94, cyano and Q1- or Q1-(Oxe2x95x90)Cxe2x80x94;
R4 is H, C1-6 alkyl, HOxe2x80x94C1-2 alkyl, Q1-, Q1-C1-3alkyl-, cyano-C1-2alkyl- or R6(R7)N C1-2alkyl-;
R5 is H, C1-2alkyl, HOxe2x80x94C1-2 alkyl or Q1-;
R6 and R7 are independently selected from H and C1-3 alkyl;
R8 is aryl;
Q1 is a 4-10 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 2 heteroatoms selected from O and N, and is optionally substituted with halo, C1-2 alkyl, hydroxy, amino, R6(R7)N C1-2alkyl- or R6(R7)NC1-2alkyl-Oxe2x80x94;
Y5, Y6, Y7 and Y8 are hydrogen;
Y1, Y2, Y3 and Y4 are independently selected from hydrogen, halo, C1-3 alkyl, C1-3 alkyl-Oxe2x80x94, C1-2 alkylthio, Q1-, R6(R8)Nxe2x80x94, R6N(R7)C(xe2x95x90O)xe2x80x94, C1-2 alkyl-O(Oxe2x95x90)CCHxe2x95x90CHxe2x80x94, Q1-(Oxe2x95x90)CNHxe2x80x94 and R6OC(xe2x95x90O)xe2x80x94, wherein said C1-3alkyl is optionally substituted with up to 2 substituents selected from Q1-, Q2-, R6(R7)Nxe2x80x94, cyano, hydroxy and R6(R7)NC(xe2x95x90O)xe2x80x94; and
Q2 is phenyl or pyridyl being optionally substituted with halo, C1-2 alkyl-, hydroxy, C1-2 alkyl-Oxe2x80x94, nitro, amino, cyano, R6(R7)Nxe2x80x94C1-2alkyl- or R6(R7)Nxe2x80x94C1-2alkyl-Oxe2x80x94, R6(R7)N(Oxe2x95x90)Cxe2x80x94 or R6O(Oxe2x95x90)Cxe2x80x94.
Much preferred compounds of this invention are those of the formula (I) wherein R1 is C1-2 alkyl;
R2 is H or amino;
R3 is H, halo-CH2xe2x80x94, R4(R5)NCH2xe2x80x94, R6(R7)NC(xe2x95x90O)CH2xe2x80x94, cyano-CH2xe2x80x94, Q1CH2xe2x80x94, Q1-(Oxe2x95x90)CCH2xe2x80x94, C2-6 alkyl or Q1-, wherein said C2-6 alkyl is optionally substituted with up to 3 substituents selected from halo, methyl, R4(R5)N, C1-2 alkylsulfonylamino, C1-2 alkylthio, R6(R7)NC(xe2x95x90O)xe2x80x94, cyano, Q1- and Q1-(Oxe2x95x90)Cxe2x80x94;
R4 is H, C1-6 alkyl, HOxe2x80x94C1-2 alkyl, phenyl-C1-3alkyl-, pyridyl-C1-3alkyl-, cyano-C1-2alkyl- or R6(R7)N C1-2alkyl-;
R5 is H, C1-2alkyl, HOxe2x80x94C1-2 alkyl or Q1-;
R6 and R7 are independently selected from H, methyl or ethyl
R8 is phenyl;
Q1 is phenyl, piperidyl, morpholino, pyridyl, benzimidazolyl, pyrrolidinyl, azetidinyl, diazepanyl or tetrahydroisoquinolyl being optionally substituted with halo, C1-2 alkyl, hydroxy, amino, R6(R7)N C1-2alkyl- or R6(R7)N C1-2alkyl-Oxe2x80x94;
Y5, Y6, Y7 and Y8 are hydrogen;
Y1, Y2, Y3 and Y4 are independently selected from hydrogen, halo, C1-3 alkyl, C1-3 alkyl-Oxe2x80x94, C1-2 alkylthio, Q1-, R6(R8)Nxe2x80x94, R6N(R7)C(xe2x95x90O)xe2x80x94, C1-2 alkyl-O(Oxe2x95x90)CCHxe2x95x90CHxe2x80x94, Q1-(Oxe2x95x90)CNHxe2x80x94 and R6OC(xe2x95x90O)xe2x80x94, wherein said C1-3alkyl is optionally substituted with up to 2 substituents selected from Q1, Q2-, R6(R7)Nxe2x80x94, cyano, hydroxy and R6(R7)NC(xe2x95x90O)xe2x80x94; and
Q2 is phenyl or pyridyl being optionally substituted with halo, C1-2 alkyl-, hydroxy, C1-2 alkyl-Oxe2x80x94, nitro, amino, cyano, R6(R7)Nxe2x80x94C1-2alkyl-, R6(R7)Nxe2x80x94C1-2 alkyl-Oxe2x80x94, R6(R7)N(Oxe2x95x90)Cxe2x80x94 or R6O(Oxe2x95x90)Cxe2x80x94.
Also, preferred compounds of this invention are those of the formula (I) wherein R1 is methyl
R2 is H or amino;
R3 is hydrogen, ethyl, butyl, hexyl, iodopentyl, carbamoylmethyl, methylthioethyl, (N,N-dimethylamino)ethyl, morpholinoethyl, (N,N-dimethylamino)butyl, (N,N-dimethylamino)hexyl, methansulfonylaminopropyl, (N-ethyl-N-methylamino)propyl, chloroethyl, aminoethyl, [(N,N-dimethylamino)methyl]phenyl, (N,N-dimethylamino)(methyl)propyl, (1-methyl-2-piperidinyl)ethyl, pyridylmethyl, cyanobutyl, 2-benzimidazolylmethyl, (N-methylamino)propyl, (1-methyl-2-pyrrolidinyl)ethyl, (1-azetidinyl)propyl, {N-methyl-N-[(pyridinyl)ethyl]amino}propyl, (N,N-diethylamino)propyl, [N-isopropyl-N-(methyl)aminopropyl, [N-(2-hydroxyethyl)-N-(isopropyl)amino]propyl, [N,N-bis(2-hydroxyethyl)amino]propyl, [N-(hydroxyethyl)-N-(methyl)amino]propyl, [N-ethyl-N-(propyl)aminopropyl, (4-methyl-1,4-diazepan-1-yl)propyl, [N-hexyl-N-(methyl)amino]propyl, [N-(cyanomethyl)-N-(propyl)amino]propyl, [N-[(diethylamino)ethyl]-N-(methyl)amino]propyl, [N-(cyanomethyl)-N-(methyl)amino]propyl, [N-methyl-N-(phenylethyl)amino]propyl, [N-ethyl-N-(hydroxyethyl)amino]propyl, (3,4-dihydro-2(1H)-isoquinolinyl)propyl, N-methyl-piperidyl, (N,N-dimethylamino)propyl, piperidyl, aminopropyl or cyanomethyl; and
Y1, Y2, Y3 and Y4 are independently selected from H, fluoro, chloro, bromo, methyl, ethyl, iso-propyl, aminopropyl, methoxy, benzyl, aminobenzyl, hydroxybenzyl, chlorobenzyl, cyanobenzyl, methoxybenzyl, (N,N-dimethylaminoethoxy)benzyl, nitrobenzyl, aminomethylbenzyl, aminoethylbenzyl, carbamoylbenzyl, carboxybenzyl, anilino, benzoylamino, hydroxy(phenyl)methyl, phenyl, aminophenyl, hydroxyphenyl, cyanoethyl, pyridylmethyl and ethoxycarbonylethenyl.
Also, preferred compounds of this invention are those of the formula (I) wherein R1 is methyl;
R2 is H or amino;
R3 is H, ethyl, n-butyl, n-hexyl, 5-iodopentyl, carbamoylmethyl, 2-methylthioethyl, 2-(N,N-dimethylamino)ethyl, 2-morpholinoethyl, 4-(N,N-dimethylamino)butyl, 6-(N,N-dimethylamino)hexyl, 3-methansulfonylaminopropyl, 3-(N-ethyl-N-methylamino)propyl, 2-chloroethyl, 2-aminoethyl, 4-[(N,N-dimethylamino)methyl]phenyl, 3-(N,N-dimethylamino)-2-methylpropyl, 2-(1-methyl-2-piperidinyl)ethyl, 3-pyridylmethyl, 4-cyanobutyl, 4-(1H-benzimidazol-2-ylmethyl), 3-(N-methylamino)propyl, 2-(1-methyl-2-pyrrolidinyl)ethyl, 3-(1-azetidinyl)propyl, 3-{N-methyl-N-[2-(2-pyridinyl)ethyl]amino}propyl, 3-(N,N-diethylamino)propyl, 3-[N-isopropyl-N-(methyl)amino]propyl, 3-[N-(2-hydroxyethyl)-N-(isopropyl)amino]propyl, 3-[N,N-bis(2-hydroxyethyl)amino]propyl, 3-[N-(2-hydroxyethyl)-N-(methyl)amino]propyl, 3-[N-ethyl-N-(propyl)amino]propyl, 3-(4-methyl-1,4-diazepan-1-yl)propyl, 3-[N-hexyl-N-(methyl)amino]propyl, 3-(N-cyanomethyl-N-propyl)aminopropyl, 3-[N-[2-(Nxe2x80x2,Nxe2x80x2-diethylamino)ethyl]-N-(methyl)amino]propyl, 3-[(N-cyanomethyl-N-methyl)amino]propyl, 3-[N-methyl-N-(2-phenylethyl)amino]propyl, 3-[N-ethyl-N-(2-hydroxyethyl)amino]propyl, 3-(3,4-dihydro-2(1H)-isoquinolinyl)propyl, N-methyl-4-piperidyl, 3-(N,N-dimethylamino)propyl, 4-piperidyl, 3-aminopropyl, cyanomethyl or 2-benzimidazolylmethyl;
Y1 is H, methyl, ethyl, propyl, aminophenyl, hydroxyphenyl, methoxy, fluoro or chloro;
Y2 is hydrogen, methyl, ethyl, propyl, benzyl, chlorobenzyl, benzoylamino, hydroxybenzyl, methoxybenzyl, (N,N-dimethylaminoethoxy)benzyl, aminopropyl, anilino, nitrobenzyl, aminomethylbenzyl, (aminoethyl)benzyl, aminobenzyl, cyanobenzyl, hydroxy(phenyl)methyl, hydroxyphenyl, cyanoethyl, pyridylmethyl, carbamoylbenzyl, carboxybenzyl, ethoxycarbonylethenyl or fluoro;
Y3 is hydrogen, ethyl, methyl, methoxy or fluoro; and
Y4 is hydrogen, chloro, fluoro, bromo, methyl, ethyl, methoxy or phenyl.
Also, preferred compounds of this invention are those of the formula (I) wherein R1 is methyl;
R2 is H;
R3 is H, N-methyl-4-piperidyl, 3-N,N-dimethylpropyl, 4-piperidyl, 3-aminopropyl, cyanomethyl or 2-benzimidazolylmethyl;
Y1 is H, ethyl, 4-aminophenyl, iso-propyl, 4-hydroxyphenyl, methoxy or fluoro;
Y2 is hydrogen, 4-chlorobenzyl, benzoylamino, 3-chlorobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, benzyl, 3-aminopropyl, anilino, 4-hydroxybenzyl, 3-nitrobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, methyl, 2-aminomethylbenzyl, 2-(2-aminoethyl)benzyl, 2-aminobenzyl, 2-methoxybenzyl, 3-aminobenzyl, 3-aminomethylbenzyl, 4-cyanobenzyl, hydroxy(phenyl)methyl, 2-hydroxyphenyl (3-hydroxyphenyl, 2-cyanoethyl, ethyl, 3-pyridylmethyl, 3-carbamoylbenzyl, 3-carboxybenzyl, ethoxycarbonylethenyl, 2-carbamoylbenzyl or fluoro;
Y3 is hydrogen, methoxy or fluoro; and
Y4 is hydrogen, chloro, fluoro, bromo or ethyl.
Also, preferred compounds of this invention are those of the formula (I) wherein the dashed lines represent double bonds
R1 is methyl;
R2 is H;
R3 is H;
Y1 is H, ethyl or 4-aminophenyl;
Y2 is H, 4-chlorobenzyl, benzoylamino, 3-chlorobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, benzyl, 3-aminopropyl, anilino, 4-hydroxybenzyl, 3-nitrobenzyl, 3-methoxybenzyl or 2-chlorobenzyl;
Y3 is H;
Y4 is H; and
Y5, Y6, Y7 and Y8 are absence.
Preferred individual compounds of this invention are: 7-(4-chlorobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
N-(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)benzamide;
7-(3-chlorobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
sodium 2-[[1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one]-7-yl-methyl]phenoxide;
7-(3-hydroxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
7-(4-methoxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
8-ethyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
7-benzyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
8-(4-aminophenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one hydrochloride;
7-(3-aminopropyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]-quinolin-9-one hydrochloride;
7-anilino-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]-quinolin-9-one;
1-methyl-7-(3-nitrobenzyl)-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
7-(3-methoxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
7-(2-chlorobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
7-[2-(aminomethyl)benzyl]-1-methyl-1,4-dihydro-9h-pyrazolo[4,3-b]quinolin-9-one hydrochloride; and
7-[2-(2-aminoethyl)benzyl]-1-methyl-1,4-dihydro-9h-pyrazolo[4,3-b]quinolin-9-one hydrochloride;
and salts thereof.
Most preferred individual compounds of this invention are: 7-(4-chlorobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
N-(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)benzamide;
7-(3-chlorobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
sodium 2-[[1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one]-7-yl-methyl]phenoxide;
7-(3-hydroxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
7-(4-methoxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
8-ethyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one; and
7-benzyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one;
and salts thereof.
General Synthesis
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, C1 to C4, Y1 to Y8, R1 to R8, Q1 and Q2 in the reaction Schemes and discussion that follow are defined herein before.
The pyrazoloquinolinone compounds of Formula (I) of this invention may be prepared by a variety of synthetic methods known to those skilled in the art. 
In a desired reaction step of the processes described hereafter, hydroxy or amino groups protection and removal of the hydroxy or amino protecting groups with reactants and reagents used may be carried out according to known procedures such as those described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley and Sons, 1991). Typical hydroxy or amino protecting groups include benzyl, C2H5OC(xe2x95x90O)xe2x80x94, benzyloxycarbonyl represented as Z and t-But-Oxe2x80x94C(xe2x95x90O)xe2x80x94 represented as t-Boc or Boc.
Reaction Scheme 1 illustrates a method for the preparation of the compound of formula (I) wherein R3 is H, Y5 to Y8 are absent and the dashed lines represent double bond. (hereinafter represented by Formula (Ia)). 
Compound (Ia) may be prepared through a process(Route 1) comprising:
(a) a coupling reaction of a compound of formula 1-1 with a pyrazolecarboxlic acid derivative 1-2 wherein X is a leaving group such as halo, mesylate(OMs) or tosylate(OTs) to give a compound of formula 1-3;
(b) cyclization of the resulting anilinopyrazole compound of formula 1-3 in the presence of a cyclizing reagent to give a tricyclic compound of formula 1-4 wherein L1 is halogen; and
(c) hydrolysis of the compound of formula 1-4 under the acidic condition to give a pyrazoloquinolinone compound of formula (Ia).
Each reaction step is described more specifically as follows:
(a) Coupling: The coupling reaction (a) may be carried out in the absence of, or presence of a base in a reaction inert solvent or without solvent. Preferred bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride; and an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine. Preferred reaction inert solvents include, but are not limited to, water, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, tetrahydrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) and mixtures thereof. Preferably, the reaction is conducted in the presence of a metal catalyst. Preferred metal catalysts include, for example, copper and nickel. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 50 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(b) Cyclization: The compound of formula 1-3 may be cyclized to form a tricyclic compound by any synthetic procedure applicable to structure-related compounds known to those skilled in the art (for example, see Author Chem. Heterocycl. Compd(Engl. Transl.), 1984; pp918 and ibid., 1985, pp905). When L1 is Cl, a suitable cyclizing reagent is, for example, phosphoryl chloride, thionyl chloride or oxalyl chloride. The reaction may be carried out at a temperature in the range from of 0xc2x0 C. to 250xc2x0 C., preferably in the range of 50xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed. The reaction may be carried out in a reaction inert solvent, such as dichloroethane.
(c) Hydrolysis: The hydrolysis of the compound of formula 1-4 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with acid in the presence or absence of a reaction inert solvent. Preferred acids include, for example, acetic acid, hydrochloric acid, trifluoroacetic acid or sulfuric acid. Preferred reaction inert solvents include, for example, water, aqueous tetrahydrofuran(THF), aqueous DMF or the mixture of them. Reaction temperatures are generally in the range of 0xc2x0 C. to 200xc2x0 C., preferably in the range of 50xc2x0 C. to the 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Alternatively, the compound of formula (Ia) may be prepared from the compound of formula (1-3) directly(Route 2 in Scheme 1). The compound of formula 1-3 may be treated with a condensing agent to give a pyrazoloquinolinone compound of Formula (Ia). Condensing agents include, for example, polyphosphoric acid, Lewis acids and proton acids. Suitable condensing agents include, for example, polyphosphoric acid, aluminum chloride or sulfuric acid. The condensation may be carried out in the presence or absence of a reaction inert solvent. In the absence of a reaction inert solvent, reaction temperatures are generally in the range of 0xc2x0 C. to 200xc2x0 C., preferably in the range of 50xc2x0 C. to the 150xc2x0 C., but if necessary, lower or higher temperature can be employed. In the presence of a reaction inert solvent, preferred reaction inert solvents include, dichloromethane, dichloroethane or nitrobenzene. Reaction temperatures are generally in the range of 0xc2x0 C. to reflux temperature, preferably in the range of 0xc2x0 C. to the 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The compound of formula Ia may also be prepared by a method as shown in Scheme 2.
Compound (Ia) may be prepared through a process comprising:
(a) acylation of a compound of formula 2-1 with a benzoyl halide derivative 2xe2x80x942 wherein X is halo, such as chloro or bromo to give a compound of formula 2-3;
(b) reduction of the nitro group in the compound of formula 2-3 to give a anilino compound of formula 2-4; and
(c) cyclization of the resulting benzoylpyrazole compound of formula 2-4 in the presence of a metal catalyst to give a tricyclic compound of formula (Ia).
Each reaction step is described more specifically as follows:
(a) Acylation: Firstly, the compound of the formula 2-1 may be treated with a base to obtain a carbanion. Preferred bases include, for example, alkyllithium, aryllithium and lithium diisopropylamide(LDA). More preferred bases may be lithium diisopropylamide. The treatment with a base may be carried out in the presence of a reaction inert solvent. Preferred reaction inert solvents include, for example, THF, dialkylether and mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92120xc2x0 C. to 150xc2x0 C., preferably in the range of xe2x88x92100xc2x0 C. to 50xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Then, the resulting carbanion may be treated with an acylhalide compound of formula 2xe2x80x942 to provide a compound of formula 2-3.
(b) Reduction: Then the resulting compound of formula 2-3 may be subjected to reduction to give the compound of formula 2-4. The reduction may be carried out in the presence of a suitable reducing agent in a reaction inert solvent or without solvent. Preferred reducing agents include, for example, Fe, Sn or Zn. When a reducing reagent is Fe, Sn or Zn, if desired, the reaction is carried out under acidic conditions in the presence of water. Preferred reaction inert solvents include, for example, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reduction may also be carried out under known hydrogenation conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. Preferred metal catalysts include, for example, nickel catalysts such as Raney nickel, palladium catalysts such as Pdxe2x80x94C, platinum catalysts such as PtO2, or ruthenium catalysts such as RuCl2(Ph3P)3. Preferred reaction inert solvents include, for example, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) Cyclization: The compound of formula 2-4 may be cyclized to form pyrazoloquinolinone by treating the compound of formula 2-4 with a base in the presence of metal catalyst. Preferred bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine. Preferred metal catalysts include, for example, copper and nickel. The reaction may be carried out in a reaction inert solvent. Suitable reaction inert solvents include, for example, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. The reaction may be carried out at a temperature in the range from of 0 to 250xc2x0 C., preferably in the range of 50 to 200xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
As depicted in Scheme 2xe2x80x942, the intermediate compound of formula 2-3 may be prepared by an alternative route. 
After treating a pyrazole compound of formula 2xe2x80x942 with a base, the anion obtained may be reacted with a benzaldehyde compound of formula 2-5 instead of the acylhalide compound of formula 2xe2x80x942 to give a alcohol compound of formula 2-6. This compound may be subjected to oxidation to give the compound of formula 2-3. The oxidation may be carried out in the presence of or absence of a suitable oxidizing agent in a reaction inert solvent or without solvent. Preferred oxidizing agents include, for example, manganese oxide, chromium oxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Preferred reaction inert solvents include, for example, acetone, dimethylsulfoxide(DMSO), acetic anhydride, tetrahydrofuran, 1,4-dioxane or mixtures thereof. Reaction temperatures are generally in the range of 0xc2x0 C. to reflux temperature, preferably in the range of 20xc2x0 C. to reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 3 days, preferably from 20 minutes to 2 days, however shorter or longer reaction times, if necessary, can be employed.
The intermediate benzaldehyde compound of formula 2-5 may be prepared from a compound of formula 2-0, wherein X1, X2, X3 and X4 are independently selected from H, Br or O-trifluoromethanesulfonate(OTf), by a coupling reaction using an appropriate coupling reagent of formula 2-8, wherein Rt is C1-5 alkyl and Yt is independently selected from Y1, Y2, Y3 and Y4, in the presence of catalysts. Suitable coupling reagents include aryl or heteroaryltrialkylstannane, aryl or heteroarylboronic acid, or arylalkyl or heteroarylalkyltrialkylstannane. Suitable catalysts include, for example, tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium. The reaction may be carried out in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, hexamethylphosphoramide(HMPA) or dimethoxyethane(DME). Reaction temperatures are generally in the range of 0xc2x0 C. to 250xc2x0 C., preferably in the range of 20xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to a day, however shorter or longer reaction times, if necessary, can be employed.
The compound of formula (Ia) also may be prepared from the compound of formula 3-1 through the compound of formula 1-4 as shown in Scheme 3.
The compound of formula 3-1 may be reacted with aryl or heteroaryltrialkylstannane, aryl or heteroarylboronic acid, or arylalkyl or heteroarylalkyltrialkylstannane in the presence of catalysts to give the compound of formula 1-4. Suitable coupling reagents include aryl or heteroaryltrialkylstannane, aryl or heteroarylboronic acid, or arylalkyl or heteroarylalkyltrialkylstannane. Suitable catalysts include, for example, tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium. If desired, the reaction may be carried out in the presence of a base, such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like. The reaction may be carried out in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, hexamethylphosphoramide(HMPA) or dimethoxyethane(DME). Reaction temperatures are generally in the range of 0xc2x0 C. to 250xc2x0 C., preferably in the range of 20xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to a day, however shorter or longer reaction times, if necessary, can be employed. The obtained chlorinated compound of formula 1-4 may be hydrolyzed under the acidic conditions to give the compound of formula Ia. Suitable acids include, for example, acetic acid, hydrochloric acid, trifluoroacetic acid or sulfuric acid. Preferred reaction inert solvents include, for example, water, aqueous tetrahydrofuran(THF), aqueous DMF or the mixture of them. Reaction temperatures are generally in the range of 0xc2x0 C. to 200xc2x0 C., preferably in the range of 50xc2x0 C. to the 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 4 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nPhOH and n is 0 to 4 (hereinafter represented by Formula (Ia2)). The compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nPhOC1-4alkyl(hereinafter represented by Formula (Ia1)) may be prepared according to the same procedure as mentioned before. 
The compound of formula Ia1 may be dealkylated under the standard conditions to give the compound of formula Ia2. Dealkylation of the compound of formula Ia1 may be carried out according to a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for Phenolsxe2x80x9d, in Protective Groups in Organic Synthesis, 3rd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 246-275). For example, the compound of formula Ia1 may be treated with a proton and/or Lewis acid such as hydrogen bromide or aluminum chloride in a suitable solvent such as water, acetic acid or dichloromethane. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to 200xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 5 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nPh(CH2)nNH2(hereinafter represented by Formula (Ia4)). The compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nPh(CH2)nxe2x80x94N-phthalimidolyl (hereinafter represented by Formula (Ia3)) may be prepared according to the same procedure as mentioned before. 
Cleavage of N-phthalimide in the compound of formula Ia3 may be carried out according to a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the amino groupxe2x80x9d, in Protective Groups in Organic Synthesis, 3rd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 564-566). For example, the compound of formula Ia3 may be treated with a hydrazine derivative, such as hydrazine, methylhydrazine, and phenylhydrazine in a suitable solvent such as water or ethanol. Reaction temperatures are generally in the range of xe2x88x9250xc2x0 C. to 200xc2x0 C., preferably in the range of 0xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 1 day, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 6 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nQtNH2(Qt is aryl or heteroaryl, hereinafter represented by Formula (Ia6)). The compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nQtNO2 (hereinafter represented by Formula (Ia4)) may be prepared according to the same procedure as mentioned before. 
The reduction may be carried out in the presence of a suitable reducing agent in a reaction inert solvent or without solvent. A preferred reducing agent is selected from, for example, LiAlH4, LiBH4, Fe, Sn or Zn. When a reducing reagent is Fe, Sn or Zn, if desired, the reaction is carried out in the presence of ammonium chloride. Preferred reaction inert solvents include, for example, water, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 12 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 7 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nPh(CH2)mCONH2 and m is 0 to 3 (hereinafter represented by Formula (Ia8), xe2x80x94(CH2)nPh(CH2)mCO2H (hereinafter represented by Formula (Ia9)) or xe2x80x94(CH2)nPh(CH2)mCH2NH2(hereinafter represented by Formula (Ia10)). The compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94CN (hereinafter represented by Formula (Ia7)) may be prepared according to the same procedure as mentioned before. 
The hydrolysis of the compound of formula Ia7 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with a base. Preferred bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or halide, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate or lithium iodide, in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, for example, water, methanol, ethanol, isopropanol, tert-butylalcohol, tetrahydrofuran (THF), DMSO, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 12 hours, however shorter or longer reaction times, if necessary, can be employed.
The hydrolysis of the compound of formula Ia8 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with an acid or an alkaline. Preferred acids include, for example, hydrochloric acid, acetic acid or sulfuric acid in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, for example, water, methanol, ethanol, isopropanol, tert-butylalcohol, tetrahydrofuran (THF), DMSO, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed.
The reduction of the compound of formula Ia7 may be carried out under known hydrogenation conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under basic conditions, for example, in the presence of ammonia. Preferred metal catalysts include, for example, nickel catalysts such as Raney nickel, palladium catalysts such as Pdxe2x80x94C, platinum catalysts such as PtO2, or ruthenium catalysts such as RuCl2 (Ph3P)3. Preferred reaction inert solvents include, for example, methanol, ethanol, ethyl acetate, THF, 1,4-dioxane or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 12 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 8 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94NHR8(hereinafter represented by Formula (Ia11)). The compound of formula 8-1 may be prepared according to the same procedure as described in Scheme 1, 4 or 6.
The obtained compound of formula 8-1 may be reacted with boronic acid derivative in the presence of catalysts to provide N-substituted compound of formula 8-2. Preferred catalysts include, for example, copper acetate or copper oxide. This reaction may be carried out in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, for example, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixtures thereof. If desired, the reaction may be carried out in the presence of base, such as triethyl amine, diisopropylethylamine, or N-methylmorpholine. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed. The hydrolysis of obtained compound of formula 8-2 may be carried out according to the conditions illustrated in Scheme 1 to give the compound of formula Ia11.
Reaction Scheme 9 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94NHCOQ1(hereinafter represented by Formula (Ia12)). The compound of formula 9-1(8-1) may be prepared according to the same procedure as described in Scheme 1, 4 or 6.
The obtained compound of formula 9-1(8-1) may be reacted with acylating agents, such as acid chloride or acid anhydride in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, for example, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed. The hydrolysis of obtained compound of formula 9-2 may be carried out according to the conditions illustrated in Scheme 1 to give the compound of formula Ia12.
Reaction Scheme 10 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)2R10(hereinafter represented by Formula (Ia13)). The compound of formula 10-1, wherein X is halo or OTf, may be prepared according to the same procedure as described in Scheme 1, 4 or 6.
The obtained compound of formula 10-1 may be reacted with terminal alkene derivative, wherein R10 is CN, CO2R6 or aryl, in the presence of a reaction inert solvent. The reaction may be carried out in the presence of a catalyst. Suitable catalysts include, for example, palladium acetate or palladium chloride. Preferred reaction inert solvents include, for example, DMF, acetonitrile, methanol or mixtures thereof. If desired, the reaction may be carried out in the presence of tri-o-tolylphosophine and triethylamine. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the 200xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed. The hydrolysis of obtained compound of formula 10-2 may be carried out according to the conditions illustrated in Scheme 1 to give the compound of formula 10-3. The reduction of the compound of formula 10-3 may be carried out under known hydrogenation conditions in the presence of a metal catalyst under hydrogen atmosphere. A preferred metal catalyst is selected from, for example, palladium catalysts such as Pdxe2x80x94C, platinum catalysts such as PtO2, or ruthenium catalysts such as RuCl2 (Ph3P)3. Preferred reaction inert solvents include, for example, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 11 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94CH(OH)Q1(hereinafter represented by Formula (Ia16)). The compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94CH2Q1 (hereinafter represented by Formula (Ia14)) may be prepared according to the same procedure as described in Scheme 1 or 2.
This compound may be subjected to oxidation to give the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(Cxe2x95x90O)Q1 (hereinafter represented by Formula (Ia15)). The oxidation may be carried out in the presence of or absence of a suitable oxidizing agent in a reaction inert solvent or without solvent. Preferred oxidizing agents include, for example, manganese oxide, chromium oxide, selenium dioxide and ceric ammonium nitrate (CAN). Preferred reaction inert solvents include, for example, water, ethanol, acetone, dimethylsulfoxide(DMSO), acetic anhydride, acetonitrile or mixtures thereof. Reaction temperatures are generally in the range of to xe2x88x9250xc2x0 C. to reflux temperature, preferably in the range of xe2x88x9220xc2x0 C. to reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 3 days, preferably from 20 minutes to 2 days, however shorter or longer reaction times, if necessary, can be employed. The obtained compound of formula Ia15 may be reacted with halogenating reagent to give the compound of formula 11-1. In case of L1 is Cl, a suitable halogenating reagent is, for example, phosphoryl chloride, thionyl chloride or oxalyl chloride. The reaction may be carried out at a temperature in the range from of 0xc2x0 C. to 250xc2x0 C., preferably in the range of 50xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 12 hours, however shorter or longer reaction times, if necessary, can be employed. The reaction may be carried out in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, acetonitrile, dichloromethane or toluene. Then the resulting compound of formula 11-1 may be subjected to reduction to give the compound of formula 11-2. The reduction may be carried out in the presence of a suitable reducing agent in a reaction inert solvent or without solvent. Preferred reducing agents include, for example, NaBH4, LiAlH4 or LiBH4. Preferred reaction inert solvents include, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 150xc2x0 C., preferably in the range of xe2x88x9220 to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed. The hydrolysis of the obtained compound of formula 11-2 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with acid in the presence or absence of a reaction inert solvent. Preferred acids include, for example, acetic acid, hydrochloric acid, trifluoroacetic acid or sulfuric acid. Preferred reaction inert solvents include, for example, water, aqueous tetrahydrofuran(THF), aqueous DMF or the mixture of them. Reaction temperatures are generally in the range of 0xc2x0 C. to 200xc2x0 C., preferably in the range of 50xc2x0 C. to the 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 12 illustrates a method for the preparation of the compound of formula (Ia). The compound of formula 12-1 wherein at least one of X1, X2, X3 and X4 is halo or OTf may be prepared according to the same procedure as described in Scheme 1 or 2.
This compound may be subjected to coupling reaction using appropriate coupling reagents of formula 12-2, wherein Yt is independently selected from Y1, Y2, Y3 and Y4(with the proviso Yt is not H) in the presence of catalysts. Suitable coupling reagents include aryl or heteroaryltrialkylstannane, aryl or heteroarylboronic acid, arylalkyl or heteroarylalkyltrialkylstannane, or arylalkyl or heteroarylalkyltrialkylboronic acid. Suitable catalysts include, for example, tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium. If desired, the reaction may be carried out in the presence of halogenomethal, such as lithium chloride. The reaction may be carried out in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, hexamethylphosphoramide(HMPA), 1,4-dioxane, dimethoxyethane(DME) or N,N-dimethylformamide. Reaction temperatures are generally in the range of to 0xc2x0 C. to 250xc2x0 C., preferably in the range of 20xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to a day, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 13 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is xe2x80x94(CH2)nPhOC1-4alkyl (hereinafter represented by Formula (Ia17)). The compound of formula (Ia2) may be prepared according to the same procedure as described in Scheme 2.
This compound may be treated with appropriate optionally substituted alkyl halides or alkyl mesylate in the presence of a base. Suitable bases include, for example, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydride (NaH) or potassium t-butoxide. This reaction may be carried out in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, acetone, DME, THF or DMF. Reaction temperatures are generally in the range of xe2x88x9250xc2x0 C. to 200xc2x0 C., preferably in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 12 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 14 illustrates a method for the preparation of the compound of formula (Ia0). The compound of formula (Ia) may be prepared according to the same procedure as described in Scheme 1 or 2.
This compound may be subjected to N-alkylation to give the compound of formula (Ia0). This compound may be treated with appropriate optionally substituted C1-8alkylM or Q1M(M is halogen or leaving group such as xe2x80x94O-mesyl(OMs), xe2x80x94O-tosyl(OTs) or OTf) in the presence of a base. Suitable bases include, for example, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydride (NaH) or potassium t-butoxide. This reaction may be carried out in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, acetone, DME, THF, DMSO or DMF. Reaction temperatures are generally in the range of xe2x88x9250xc2x0 C. to 200xc2x0 C., preferably in the range of xe2x88x9220xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 3 days, preferably from 20 minutes to 2 days, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 15 illustrates a method for the preparation of the compound of formula (Ia) wherein R3 is xe2x80x94C1-8alkyl-N(R5)R4 (hereinafter represented by Formula (Ia19)). The compound of formula (Ia) wherein R3 is xe2x80x94C1-8alkyl-X(X is halo or leaving group)(hereinafter represented by Formula (Ia18)) may be prepared according to the same procedure as described in Scheme 1 or 2.
This compound may be treated with HN(R5)R4 in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, methanol, ethanol, THF, DMSO or DMF. Reaction temperatures are generally in the range of 0xc2x0 C. to 200xc2x0 C., preferably in the range of 20xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 12 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 16 illustrates a method for the preparation of the compound of formula (Ia) wherein R3 is xe2x80x94C1-8alkyl-NH2 (hereinafter represented by Formula (Ia21)) through the azide compound of formula (Ia) wherein R3 is xe2x80x94C1-8alkyl-N3 (hereinafter represented by Formula (Ia20)). 
The nucleophilic displacement of leaving group of the compound of formula (Ia18) with azide may be carried out by conventional procedures in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, for example, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethylformamide (DMF), dimethoxyethane (DME), hexamethylphosphoramide (HMPA) or mixtures thereof. Preferred azide agents are selected from, for example, sodium azide or lithium azide. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from several minutes to 2 days, preferably from 20 minutes to 24 hours, however shorter or longer reaction times, if necessary, can be employed. The compound of formula Ia20 may also be prepared by the Mitsunobu reaction. The compound of formula Ia18 may be treated with diphenylphosphoryl azide (DPPA) or HN3 in the presence of dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphine reagent such as triphenylphosphine. Preferably, this reaction may be carried out in a reaction-inert solvent. Preferred reaction inert solvents include, but are not limited to, tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethoxyethane (DME), or mixtures thereof. The reduction of azide group may be carried out in the presence of a suitable reducing agent such as lithium aluminum hydride, sodium borohydride, triethyl phosphite, triphenylphosphine, zinc, dibutyl tinhydride or diboran in a reaction inert solvent selected form, but not limited to, THF, diethyl ether, methanol, ethanol and toluene. If desired, the reaction may be carried out under acidic conditions in the presence of hydrochloric acid or acetic acid. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The reduction may also be carried out under known hydrogenation conditions in the presence of a metal catalyst such as Lindler catalysts, Raney nickel catalysts, palladium catalysts or platinum catalysts (preferably Lindler catalysts, palladium catalysts or platinum catalysts). This reaction may be carried out under hydrogen atmosphere in a reaction inert solvent such as methanol, ethanol, ethyl acetate, THF or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 6 hours, however shorter or longer reaction times, if necessary, can be employed. If necessary, this reduction may be carried out under the adequate pressure in the range from about 0.5 to 10 kg/cm2, preferably in the range from 1 to 6 kg/cm2.
Reaction Scheme 17 illustrates a method for the preparation of the compound of formula (Ia) wherein R3 is xe2x80x94C1-8alkyl-NHSO2C1-4 alkyl (hereinafter represented by Formula (Ia22)). 
Sulfonylation of the amino group of the compound Ia21 may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 117-118, 379-384). More specifically, the compound of formula Ia21 may be treated with C1-4 alkylsulfonyl halide in a reaction inert solvent. Suitable reaction inert solvents include, for example, dichloromethane, dichloroethane, pyridine or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 3 days, preferably from 1 hour to 65 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 18 illustrates a method for the preparation of the compound of formula (Ia) wherein R3 is 4-piperidinyl (hereinafter represented by Formula (Ia24)) and the compound of formula (Ia) wherein R3 is 1-methyl-4-piperidinyl (hereinafter represented by Formula (Ia25)). The compound of formula (Ia23) wherein PG is suitable protecting group for amino group may be prepared according to the same procedure as described in Scheme 14.
Cleavage of the protecting group may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 3rd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 494-614). N-methylation of the compound of formula (Ia24) may be carried out under the standard conditions known to those skilled in the art to afford the compound of formula (Ia25). For example, the compound of formula (Ia24) may be treated with formalin in the presence of reducing agent in a reaction inert solvent. Suitable reducing agents include, for example, NaBH4, LiAlH4, NaBH3CNor LiBH4. Formula Ia21 may be treated with C1-4 alkylsulfonyl halide in a reaction inert solvent. Suitable reaction inert solvents include, for example, dichloromethane, DME, THF, benzene or mixtures thereof. The reaction may be carried out in the presence of an acid. Suitable acids include, for example, acetic acid, hydrochloric acid or sulfuric acid. Reaction temperatures are generally in the range of xe2x88x9250 to 100xc2x0 C., preferably in the range of xe2x88x9210 to 50xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 12 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 19 illustrates a method for the preparation of the compound of formula (Ia) wherein R3 is Q1 (Q1 is aryl or heteroaryl; hereinafter represented by Formula (Ia26)). 
The reaction may be carried out under the Ullman reaction condition in the presence of copper or copper oxide. The compound of formula Ia may be treated with a compound of Q1I in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, for example, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dimethylformamide (DMF), dimethoxyethane (DME) or mixtures thereof. Preferably, the reaction may be conducted in the presence of base. Preferred base include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 20 illustrates a method for the preparation of the compound of formula (Ia) wherein R3 is xe2x80x94(CH2)2X (X is halo; hereinafter represented by Formula (Ia29)). The compound of formula (Ia) wherein R3 is xe2x80x94(CH2)2OPG2 (PG2 is protecting group for hydroxy group; hereinafter represented by Formula (Ia27)) may be prepared according to the same procedure as described in Scheme 14.
Cleavage of the protecting group may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 3rd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 17-245). The obtained compound of formula Ia wherein R3 is xe2x80x94(CH2)2OH (hereinafter represented by Formula (Ia28)) may be reacted with halogenating reagent to give the compound of formula Ia29. When X is Cl, a suitable halogenating reagent is, for example, phosphoryl chloride or thionyl chloride. The reaction may be carried out in a reaction inert solvent. Suitable reaction inert solvents include, for example, benzene, toluene, dichloromethane, DMF, THF or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x9250 to 100xc2x0 C., preferably in the range of 0 to 50xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 21 illustrates a method for the preparation of the compound of formula (I) wherein Y1 and Y3 to Y8 are hydrogen(hereinafter represented by Formula (Ib)). 
The compound of formula 21-1 wherein R12 is C1-4alkyl may be prepared according to standard procedures known to those skilled in the art (e.g., G. A. Russell and L. O. Ochrymowycz, J. Org. Chem., 1969, 34, 3624). The compound of formula 21-2 may be prepared according to standard procedures known to those skilled in the art (e.g., J. Catalan et al., J. Heterocycl. Chem., 1985, 22, 997). These compounds may be reacted in the presence of an acid catalyst in a reaction inert solvent. Suitable acid catalysts include, for example, p-toluenesulfonic acid(p-TsOH) or camphersulfonic acid(CSA). Suitable reaction inert solvents include, for example, benzene, toluene, DMF, THF or mixtures thereof. Reaction temperatures are generally in the range of 0 to 200xc2x0 C., preferably in the range of 50 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 6 hours, however shorter or longer reaction times, if necessary, can be employed. The obtained imino compound of formula 21-3 may be cyclized under the heating conditions in a reaction inert solvent or without solvent. Suitable reaction inert solvents include, for example, xylene, diphenylether or mixtures thereof. Reaction temperatures are generally in the range of 0 to 300xc2x0 C., preferably in the range of 150 to 250xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 0.5 hour to 3 hours, however shorter or longer reaction times, if necessary, can be employed.
The starting materials 1-1, 1-2, 2-1, 2-0, 2-2, 3-1 and the other reactants are known or commercially available compounds, or may be prepared according to known procedures for a person skilled in the art.
The present invention includes salt forms of the compounds (I) as obtained above. Certain compounds of the present invention are capable of forming pharmaceutically acceptable non-toxic cations. Pharmaceutically acceptable non-toxic cations of compounds of formula (I) may be prepared by conventional techniques by, for example, contacting said compound with a stoichiometric amount of an appropriate alkali or alkaline earth metal (sodium, potassium, calcium and magnesium) hydroxide or alkoxide in water or an appropriate organic solvent such as ethanol, isopropanol, mixtures thereof, or the like.
The bases which are used to prepare the pharmaceutically acceptable base addition salts of the acidic compounds of this invention of formula (I) are those which form non-toxic base addition salts, i.e., salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benethamine(i.e., N-benzyl-2-phenylethylamine), benzathine(i.e., N,N-dibenzylethylenediamine), choline, diolamine(i.e., diethanolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumine(i.e., N-methylglucamine), nicotinamide, olamine(i.e., ethanolamine), ornithine, procaine, proline, pyridoxine, serine, tyrosine, valine and tromethamine(i.e., tris or tris(hydroxymethyl)aminomethane). The base addition salts can be prepared by conventional procedures.
Insofar as the certain compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, adipate, aspartate camsylate, (i.e., 1,2-ethanedisulfonate), estolate(i.e., laurylsulfate), gluceptate(i.e., gluscoheptonate), gluconate, 3-hydroxy-2-naphthoate, xionofoate(i.e., 1-hydrroxy-2-naphthoate), isethionate,(i.e., 2-hydroxyethanesulfonate), mucate(i.e., galactarate), 2-naphsylate(i.e., naphthalenesulphonate, stearate, cholate, glucuronate, glutamate, hippurate, lactobionate, lysinate, maleate, mandelate, napadisylate, nicatinate, polygalacturonate, salicylate, sulphosalicylate, tannate, tryptophanate, borate, carbonate, oleate, phthalate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts can be prepared by conventional procedures.
The compounds of formula (I) of this invention may contain one or more asymmetric centers. Thus, the compounds can exist in separated (+)- and (xe2x88x92)-optically active forms, as well as in the racemic form thereof. The present invention includes all such forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation in the preparation of the final product or its intermediate.
In addition, when the compounds of this invention form hydrates or solvates they are also within the scope of this invention.
The pyrazoloquinolinone compounds of this invention have protein kinase C (PKC) inhibitory activities, and thus are useful for the treatment of neuropathic pain, acute or chronic inflammatory pain, auditory deficiency (synaptic repair), hypertension, forcal celebral ischemia, pulmonary fibrosis, diabetes, immune disease, colonic repair, drug resistance (MDR regulation), Alzheimer, sepsis, shock, ARDS, inflammation, ischemia, gastric acid regulation, diabetic neuropathy, asthma, HIV infection, gastric ulcer or cerebral ischemia or the like in mammalian, especially human.
The compounds of the invention may prevent expression of the morphine tolerance.
Method for Assessing Biological Activities:
The PKC inhibitory activity of the compounds of this invention are determined by the following procedures.
In vitro Assays
Protein Kinase C (PKC) Assay
The assay components are in a total of 100 xcexcl, including 45 mM Tris-HCl buffer pH 7.5 (Life Technologies), 0.75 mM calcium acetate (Wako), 3.6 mM magnesium chloride (Wako), 1.875 mM DL-dithiothreitol (Sigma), 18.75 xcexcg/ml L-(xcex1-phosphatidyl-L-serine (Sigma), 1.5 xcexcg/ml phorbol 12-myristate 13-acetate (Sigma), 2.5 xcexcM biotinylated peptide (neurogranin 28-43, Asahi Techno Glass), 10 xcexcl of 1.0% aqueous DMSO or DMSO/inhibitor and 0.3 xcexcM (gamma 33P) ATP (NEN). The reaction was initiated by the addition of human recombinant PKCxcex1 (Calbiochem), PKCxcex22 (Calbiochem) or PKCxcex3 (Calbiochem or in-house preparation), incubated at room temperature for 15 minutes and stopped by adding 100 xcexcl of 5 mg/ml streptavidin SPA beads (Amersham Pharmacia Biotech) including 50 xcexcM ATP (Sigma), 5 mM EDTA (Dojindo) and 0.1% Triton X-100 (Wako) in phosphate-buffered saline (Nissui). The reaction mixture was further incubated for 15 minutes, centrifuged at 1000 rpm for 1 minute and the radioactivity was quantified by TopCount (Packard).
cAMP-Dependent Protein Kinase (PKA) Assay
The PKA assay was performed essentially as described above except for the followings. Concentration of DL-dithiothreitol was set at 187.5 xcexcM. L-xcex1-Phosphatidyl-L-serine and phorbol 12-myristate 13-acetate were not used. Human recombinant PKA and biotinylated peptide (Kemptide, Peninsula laboratories) was prepared internally and the substrate was used at 1 xcexcM.
The most preferred compounds prepared in the working examples as described below were tested by this method, and showed an IC50 value of 0.1 xcexcM to 1 xcexcM with respect to inhibitory activity.
In vivo Assays
Neuropathic Pain Model
Chronic constriction injury (CCI) model (Bennett et al., Pain 33 87 1988) was used to investigate the effect of compounds on rat neuropathic pain model. SD rats (male, 8 weeks, Nippon SLC) were used in this assay. CCI of sciatic nerve was made by tying loose ligature with 4-0 chromic gut around aciatic nerve four times with 1 mm spacing. In sham-operated mice, the nerve was exposed without ligation.
Detection of Mechanical Allodynia
Efficacy of drugs on rat neurophatic pain model was examined by using von Frey Hair test (Semmes-Weinstein Monofilaments; North Coast Medical, Inc.). (Mechanical allodynia was examined by using von Frey Hair (Semmes-Weinstein Monofilaments; North Coast Medical, Inc.). Rats were placed on a mesh floor, so that the plantar surface of the hindpaw can be stimulated from below. Each hair was applied to the midplantar of hindpaw 10 times in order of increasing stiffness. The first hair in the series that evoked at least 1 response was designated the threshold.) This test was performed 14 days after the surgery.
The pyrazoloquinolinone compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 10 mg to 500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, for example, a dosage level that is in the range of from 0.06 mg to 2 mg per kg of body weight per day is most desirably employed for treatment of inflammation.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.